DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status
Claims 14-22 and 31-41 are pending. Claims 14-22, 35-38 and 41 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species. Therefore, Claims 31-34, 39 and 40 are examined on the merits.
Election/Restrictions
Applicant’s election was made without traverse in the reply filed on 10/31/2025 of:
a. a patient population having:
i. rheumatoid arthritis as a species of arthritis;
ii. plasma as a species of blood sample;
iii. moderate-to-high disease activity signature as a species of disease activity signature, where the moderate-to-high disease activity signature includes
a) an increased level of metabolites, and
b) cysteinylglycine disulfide, mannose, beta-hydroxyisovalerate, gluconate, glucose as metabolites;
and
b. a therapeutic intervention that includes:
iv. administration of an arthritis drug and adalimumab as a species of arthritis drug.
Claim 37 is withdrawn
Claim 37 was amended to now require all recited metabolites instead of the 5 elected metabolites, namely, cysteinylglycine disulfide, mannose, beta-hydroxyisovalerate, gluconate, glucose as the metabolites. Because Claim 37 is now drawn to nonelected species, it is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species.
Information Disclosure Statement
No Information Disclosure Statement was filed with Applicant’s current amendment.
Claim Objections
Claims 31 is objected to because of the following informalities:
Claim 31, line 4: The term “having a disease activity - 28 using C-reactive protein (DAS28-CRP) score greater than 3.2” at lines 4-5 should be changed to "having a Disease Activity Score-28 with C-reactive protein (DAS28-CRP) score greater than 3.2".
Appropriate correction is required.
Withdrawn Claim Rejections
Claim 37 was rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant’s amendment and corresponding reply pertaining to the newly added limitation have overcome the improper claim dependency rejection made of record in the previous Office Action, specifically, the limitation added to claim 37 that requires the increase levels for all recited metabolites. Therefore, the rejection is withdrawn.
Claim Rejections - 35 USC § 103
New rejection, necessitated by amendment
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 31-34, 39, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over
Anderson1 et al. (J. Proteome Res. 2018, 17, 11, 3780–3790) in view of
Kempeni et al. (EP 3190124, publ. date 2017), taken further in view of
Yang et al. (PLoS One. 2015 Jul 6;10(7):e0132695. doi:10.1371/journal.pone.0132695. eCollection 2015),
Anderson2 et al. (Arthritis Care Res (Hoboken). 2012 May ; 64(5): 640–647. doi:10.1002/acr.21649)
Giustarini et al. (Clinical and Experimental Rheumatology 2005; 23: 205-212), and
HMDB metabocard entry Gluconic acid (HMDB0000625; 2017-12-07).
Claimed invention
Claim 31 is drawn to:
A method for treating a mammal having arthritis, wherein said method comprises:
determining that a blood sample from said mammal comprises a moderate-to-high disease activity signature having a Disease Activity Score-28 with C-reactive protein (DAS28-CRP) score greater than 3.2,
wherein said moderate-to-high disease signature comprises (2a) an increased level of five or more metabolites selected from the group consisting of cysteinylglycine disulfide, mannose, beta-hydroxyisovalerate, gluconate, and glucose,
and
(b) administering an arthritis drug (adalimumab) to said mammal or performing surgery to treat said arthritis.
Prior art
Anderson1 teaches metabolomic profiling in inflammatory arthritis and serum metabolite and metabolic pathways have been shown to correlate with markers of inflammation in rheumatoid arthritis (RA), e.g., CRP (Anderson1 p. 3782, second column). Anderson1 further teaches that arthritis involves altered metabolic pathways, including glycolysis and the tricarboxylic acid (TCA) cycle (Anderson1 p. 3783, second column), branched-chain amino acids (isoleucine, leucine, and valine) (Anderson1 p. 3787, first column). Anti-TNF therapy is effective for RA treatment (p. 3784, first column) and metabolomic analysis of urine from RA patients prior to commencement of anti-TNF therapy identified higher histamine, glutamine and xanthurenic acid, along with lower levels of ethanolamine as biomarkers of a good response to therapy (Anderson1 p. 3786). Anderson1 Tables 1 and 2 identifies metabolites measurable in inflammatory arthritis including glucose, mannose and 3-hydroxyisovalerate (i.e., beta-hydroxyisovalerate) and found that RA has higher leucine and glycine levels as compared to osteoarthritis (Anderson1 pp. 3783-3784). Anderson1 teaches altered metabolite levels are detected through analysis of fluid samples (e.g., serum, urine and synovial fluid - see Anderson1 p. 3782).
While Anderson1 teaches measurement of glucose, mannose, and beta-hydroxyisovalerate in RA metabolomic profiling and teaches that carbohydrate metabolism and branched-chain amino acid (BCAA) metabolism are altered in RA, Anderson1 does not expressly teach
the administration of adalimumab for RA or
measuring increased levels of the metabolites in RA including gluconate and cysteinylglycine disulfide as part of a specific five-metabolite panel.
Regarding 1) administration of adalimumab for RA:
The prior art already recognized adalimumab as an effective therapeutic for RA. For example, Kempeni establishes that tumor necrosis factor-alpha (TNFα) plays a central role in the pathophysiology of various autoimmune diseases. See Kempeni 0093. Kempeni discloses that conditions marked by elevated TNFα concentrations in the patient's biological fluids—such as serum, plasma, or synovial fluid—can be identified using an anti-TNFα antibody. See Kempeni 0089. Specifically, in rheumatoid arthritis (RA), TNFα drives tissue inflammation and joint destruction. Consequently, inhibiting this cytokine is a viable therapeutic strategy. See Kempeni 0093. As taught by Kempeni, the human anti-TNFα monoclonal antibody adalimumab (D2E7) is indicated for the treatment of RA in humans. Adalimumab binds to TNFα, inhibiting its activity, and is effective in reducing the symptoms, progression, and structural damage associated with RA. See Kempeni title, abstract; claim 1.
A person of ordinary skill in the art (POSA) would have found it obvious to administer adalimumab to RA patients because Anderson1 establishes RA as an inflammatory disease with measurable metabolic and biochemical perturbations and Kempeni teaches adalimumab is an established anti-TNFα therapy for RA and targets inflammatory mechanisms underlying the disease state described in Anderson1. The combination of Anderson1 and Kempeni merely applies a known RA therapeutic with a known patient population with RA.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Regarding 2) measuring increased levels of the elected metabolites in RA including gluconate and cysteinylglycine disulfide as part of a specific five-metabolite panel:
Anderson1 already establishes the routine practice of measuring and analyzing the levels of known metabolites in body fluids in patients treated for RA including measuring levels of glucose, mannose, and beta-hydroxyisovalerate in RA metabolomic profiling. Anderson1 also teaches that perturbations in carbohydrate metabolism and branched-chain amino acid (BCAA) metabolism are of interest in RA.
Giustarini already recognized that human cells have developed a strong antioxidant defense against pro-oxidant reactions (Giustarini, p. 206, right column). An important chemical barrier against oxidative stress damage is the redox equilibrium of sulfhydryl/disulfides, through which low molecular weight thiols can be reversibly oxidized to disulfides and/or protein mixed disulfides (reacting with cysteine residues in proteins) in response to an oxidative status (Giustarini, p. 206, middle column). Giustarini conducted a study and obtained data to determine the plasma sulfhydryl/disulfides balance in patients with active RA by analyzing all thiol redox species that had been potentially modified as a result of the disease (Giustarini, p. 206, right column). Useful information could derive from these data in that it is known that hyperhomocysteinemia is an important risk factor for vascular diseases, thrombotic events and stroke and, what is more, that cardiovascular disorders are the first cause of death in RA patients (Giustarini, paragraph bridging pp. 210 and 211). Giustarini teaches RA patients are characterized by decreased levels of thiols and increased concentration of disulfide forms of thiols (Giustarini, p. 211, middle column), with some of these parameters closely related to articular damage. Homocystine, cystine and corresponding protein-thiol mixed disulfides could be used as useful markers for the evaluation of the activity of the pathology. The possibility that an alteration in the plasma thiols/disulfides balance is a factor that concurs to the development of the disease (Giustarini, p. 211, middle column).
Yang performed metabolomic profiling of RA synovial fluid and reports detection and quantification of D-glucose and mannose, as well as the gluconate in the form of glucono-δ-lactone, in RA patient samples relative to normal controls (see Yang, p. 5; see also Table 1 at p. 7 and Table S3 attached at end of Yang). Thus, similar to Anderson1, Yang expressly discloses glucose, mannose, and a gluconate are measurable metabolites in RA patients. HMDB0000625 establishes that glucono-δ lactone is a cyclic ester of gluconic acid (see HMDB0000625, p.1). Yang expressly groups RA patients according to disease activity using DAS28>3.2 and explains that DAS28 correlates closely with clinical parameters of RA disease activity. Yang further determines metabolite concentration in inactive and active RA patients and reports that metabolite concentrations could be used as biomarkers of active RA. Thus, the prior art expressly teaches both determining metabolite levels in RA patients and stratifying such patients as having active disease using the claimed DAS28 >3.2 threshold.
Anderson2 teaches DAS28 is an established measure for determining RA disease activity and specifically recommends DAS28 calculated using either C-reactive protein (CRP) or ESR as a measure of RA disease activity. See p. 4. Anderson2 further teaches that DAS28-CRP is an available form of DAS28 (see p. 6) and provides the formula for calculating DAS28-CRP (see p. 17). Particularly, Table 3 on p. 16 identifies the disease-activity cutoffs for DAS28-CRP and discloses that a moderate to high disease activity obtains a score greater than or equal to 3.2 DAS28-CRP.
A person of ordinary skill in the art (POSA) would have found it obvious to determine whether levels of the metabolites, glucose, mannose, gluconate, 3-hydroxyisovalerate, and cysteinylglycine disulfide, are increased during RA treatment with adalimumab because Anderson1, Yang, and Giustarini teach that RA involves measurable metabolic and redox disturbances and that the recited metabolites are detectable and quantifiable in RA samples. The POSA would have found that monitoring the levels of metabolites identified during RA treatment represents a predictable application of metabolomic analysis to evaluate biochemical changes associated with therapeutic intervention. The POSA would have further found it obvious to use the known DAS28-CRP measure and its 3.2 disease activity threshold when determining the disease activity of the RA patient. The claim does not require a novel detection technique or unexpected interaction among the metabolites, but merely the determination of whether their levels increase in RA subjects.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 32 limits claim 31, wherein said mammal is a human. Kempeni teaches the active is administered to humans. See Kempeni, 0087,0088.
Claim 33 limits claim 31, wherein said arthritis is a rheumatoid arthritis. Claim 39 limits claim 31, wherein said method comprises administering said arthritis drug to said mammal. Claim 40 limits claim 39, wherein said arthritis drug is adalimumab. Kempeni teaches administration of adalimumab to treat RA. See Kempeni throughout.
Claim 34 limits claim 31, wherein said blood sample is a plasma sample. Anderson1 and Giustarini teach metabolite measurements performed on blood-derived samples including plasma, rendering obvious the limitation that the blood sample is plasma. See Kempeni 0089 and Giustarini, p. 206, right column.
Response to arguments
Applicant argues that the references do not teach determining moderate to high disease activity from metabolite levels, Yang expressly groups RA patients as inactive (DAS28<3.2 or active (DAS28>3.2) and evaluates metabolites in those groups. Anderson2 further teaches DAS28 using CRP as an established RA disease-activity measure (p. 4) and identifies DAS28 (CRP and ESR) scores of greater than or equal 3.2 as moderate to high disease activity. See Table 3 on p. 16. Thus, a POSA would have found it obvious to use the known DAS28-CRP identifying measure and >3.2 threshold when evaluating the RA-associated metabolite levels taught by the prior art. Anderson’s alleged lack of correlation with the length of disease activity does not teach away from determining the level of disease activity.
Therefore, the rejection is deemed to still be proper and is, therefore, maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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CHRIS E. SIMMONS
Examiner
Art Unit 1622
/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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